Some plants are genetically resistant to viral infection. Infection of these cultivars with a virus such as tobacco mosaic virus induces a defense response that includes the synthesis of a family of related proteins collectively known as pathogenesis-related (PR) proteins. PR proteins are relatively small (ca. 10-20 kDa), resistant to proteases, soluble in acidic buffer, and found primarily in the extracellular spaces of leaves and roots. The synthesis of PR proteins may be part of a primitive immunological response in plants including tobacco, tomato, and elder. For reviews, see Matthews, R. E. F. (1980), in Comprehensive Virology vol. 16, Plenem Press, New York, N.Y.; pp. 297-359, and van Loon, L. C. (1985) Plant Mol. Biol. 4:111-116.
Proteins with sequence homology to plant PR proteins have been identified in various insects and animals. For example, wasp, hornet, and yellow jacket venom allergens, human and rodent testes-specific antigens, and human glioma PR protein (GLIPR) are all related to plant PR proteins (King, T. P et al. (1990) Protein Seq. Data Anal. 3:263-266; Lu, G. et al. (1993) J. Immunol. 150:2823-2830; Charest, N. J. et al. (1988) Mol. Endocrinol. 2:999-1004; Kasahara, M. et al. (1989) Genomics 5:527-534; Murphy, E. V. et al (1995) Gene 159:131-135).
GLIPR was cloned from an astrocytoma cDNA library (Murphy, E. V. et al., supra). Astrocytomas, and the more malignant glioblastoma, are the most common form of tumors in the brain, accounting for more than 65% of primary human brain tumors (Morris, J. H. and Schoene, W. C. (1984) in The Pathological Basis of Disease, W. B. Saunders, Philadelphia, Pa.; pp. 1401-1456). GLIPR is expressed almost exclusively in tumors and cell lines derived from gliomas, but not in other tumors, cell lines, normal adult or fetal tissues (Murphy, E. V. et al., supra).
Normal astrocytes function as supporting cells for neurons and as immune cells in the central nervous system. Following infection, astrocytes function as antigen-presenting cells and modulate the activity of lymphocytes and macrophages (Beneviste, E. N. (1992) J. Physiol. 263:C1-C16; Merrill, J. E. (1992) Dev. Neurosci. 14:1-10). Astrocytomas, derived from glial cells of the astrocyte lineage, constitutively express many cytokines and interleukins that are normally produced only after infection by a pathogen (de Micco, C. (1989) J. Neuroimmunol. 25:93-108; Merrill, J. E., supra).
GLIPR is a small protein with a molecular weight of 24 kDa. Secondary structure analysis predicts that GLIPR is mostly .beta.-sheet. GLIPR and other PR family proteins share a conserved His-Glu-His triad of amino acid residues that are appropriately spaced to form a metal-binding domain. As other PR family proteins, GLIPR also contains the conserved domain that is characteristic of extracellular proteins.
The discovery of polynucleotides encoding human pathogenesis-related protein and the molecules themselves, provides a means to investigate tumorigenesis and the response to infection. Discovery of molecules related to human pathogenesis-related protein satisfies a need in the art by providing new diagnostic or therapeutic compositions useful in the diagnosis, prevention, and treatment of cancer, infectious diseases, and neurological disorders.